We sought to evaluate the therapeutic efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) with oral progestins for treatment of non-atypical endometrial hyperplasia (EH). Searches were conducted on PubMed, SCOPUS, and CENTRAL databases to August 2014, and reference lists of relevant articles were screened. The search was limited to articles conducted on human beings and females. The PRISMA Statement was followed. Seven randomized controlled trials (n = 766 women) were included. Main outcome measures were the therapeutic effect rate (histological response) after 3, 6, 12, and 24 months of treatment; rate of irregular vaginal bleeding; and the hysterectomy rate per woman randomized. The Cochrane Collaboration risk of bias tool was used for quality assessment. Metaanalysis was performed with fixed effects model. LNG-IUS achieved a highly significant therapeutic response rate compared with oral progestins after 3 months of treatment (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.39–3.82; P = .001, 5 trials, I 2 = 0%, n = 376), after 6 months of treatment (OR, 3.16; 95% CI, 1.84–5.45; P < .00001, 4 trials, I 2 = 0%, n = 397), after 12 months of treatment (OR, 5.73; 95% CI, 2.67–12.33; P < .00001, 2 trials, I 2 = 0%, n = 224), and after 24 months of treatment (OR, 7.46; 95% CI, 2.55–21.78; P = .0002, 1 trial, n = 104). Subgroup analysis showed evidence of highly significant therapeutic response following LNG-IUS compared with oral progestins for non-atypical simple as well as complex EH (OR, 2.51; 95% CI, 1.14–5.53; P = .02, 6 trials, I 2 = 0%, n = 290; and OR, 3.31; 95% CI, 1.62–6.74; P = .001, 4 trials, I 2 = 0%, n = 216, respectively). Compared with oral progestins, LNG-IUS achieved significantly fewer hysterectomies (OR, 0.26; 95% CI, 0.15–0.45; P < .00001, 3 trials, n = 362, I² = 42%). No difference was observed in the rate of irregular vaginal bleeding between both groups (OR, 1.12; 95% CI, 0.54–2.32; P = .76, 2 trials, n = 207, I² = 77%). Funnel plot analysis was not performed because of the relatively small number of included studies. For treatment of non-atypical EH, LNG-IUS achieves higher therapeutic effect rates and lower hysterectomy rates than oral progestins and should be offered as an alternative to oral progestins in these cases.
Endometrial hyperplasia (EH) is a histological diagnosis characterized by proliferation of endometrial glands resulting in a greater gland-to-stroma ratio than observed in normal endometrium. It is typically classified into simple or complex hyperplasia, with or without cytological atypia. Recently, among women aged 18-90 years, the overall incidence of EH was 133/100,000 woman-years and it peaks in the early 50s and early 60s. It is worth remembering that EH is a commonly seen clinical entity, presenting mainly with abnormal uterine bleeding including heavy, prolonged, or irregular perimenopausal bleeding as well as postmenopausal bleeding. Apart from this problematic symptomatology, the real clinical significance of EH is the potential risk of progression to endometrial carcinoma, which is low for women with non-atypical EH compared with women with cytologic atypia (<5% vs approximately 30%, respectively).
Unfortunately, despite a long history of our knowledge about EH, no guidelines were issued for its optimal treatment. Hysterectomy is the preferred treatment in most women with EH with atypia who are no longer interested in childbearing in view of the risk of concomitant carcinoma in up to 42.6% of cases or progression to carcinoma. Oral progestins, mainly norethisterone acetate (NET), megestrol acetate, and medroxyprogesterone acetate (MPA), are a popular therapeutic choice especially in non-atypical cases of EH. However, the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena; Bayer Schering Pharma Oy, Turku, Finland) represents an appealing option for treatment of EH without atypia and even selected cases with atypia, in view of achieving higher local progestin concentrations by many folds compared with oral therapy. A recent metaanalysis of 24 observational studies including 1001 women showed that oral progestins achieved a significantly lower pooled regression rate compared with LNG-IUS for non-atypical complex EH (66% vs 92%), but not for non-atypical simple EH. Of note, the authors admitted the poor quality of the included studies and the need for randomized controlled trials (RCTs) to generate the best evidence.
More recently, the efficacy of LNG-IUS vs oral progestins for treatment of non-atypical EH has been tested in RCTs.
In view of the aforementioned context and given that this is a clinically important area to address, this systematic review and metaanalysis was conducted to evaluate the therapeutic efficacy of LNG-IUS vs oral progestins for treatment of non-atypical EH on the basis of the available evidence so far in RCTs.
Materials and methods
The methodology of this systematic review and metaanalysis followed the PRISMA statement. The clinical question posed was: in women with non-atypical EH, does LNG-IUS represent a more effective therapy compared with oral progestin treatment?
Information sources and search strategy
An electronic search was performed using the following databases: PubMed, SCOPUS (each from inception through August 2014), and CENTRAL (Cochrane Central Register of Controlled Trials, Issue 8, 2014) with the following search terms, adjusting for each database as necessary: “endometrial hyperplasia” AND “levonorgestrel-releasing intrauterine system” OR “LNG-IUS” AND “progestins” OR “progestogens” AND “randomized trials.” The search was limited to articles conducted on human beings and females. Manual screening of references of the retrieved articles was also performed to identify other pertinent studies.
Study selection
The titles and abstracts of retrieved citations were subsequently screened for eligibility by 2 independent reviewers (H.A. and E.G.) using the following inclusion criteria: (1) women diagnosed histologically with non-atypical EH according to the World Health Classification (simple, complex, and atypical) ; (2) only RCTs that compared LNG-IUS with oral progestin treatment and reported therapeutic response after 3, 6, 12, or 24 months of treatment were included; (3) a study with multiple treatment groups including cases with atypical EH was considered, however, only information from cases with non-atypical EH was utilized; and (4) a study including different oral progestin arms or different dosage control groups was considered, however, information from the oral progestin arm with the highest therapeutic effect was utilized. Exclusion criteria were: quasi-RCTs, non-RCTs, concurrent endometrial cancer, or other malignancy. Full texts were obtained by contacting the author when it could not be obtained online.
Data extraction
The data from each included trial were extracted independently by 2 reviewers (H.A. and E.G.) on a data extraction form designed in accordance with the Cochrane Checklist of items. Details included; source, eligibility, methods, participants, interventions, outcomes, results, as well as any other important miscellaneous data. The primary efficacy outcome was the therapeutic effect rate (histological response) after 3, 6, 12, and 24 months of treatment, diagnosed according to the last endometrial biopsy by Pipelle (Laboratoire C.C.D, Paris, France) or curettage. Proliferative, secretory, inactive, or atrophic pattern endometrium was considered a therapeutic effect. Secondary clinical outcomes were rate of irregular vaginal bleeding during treatment and the hysterectomy rate. The unit of analysis was per woman randomized.
Assessment of risk of bias
The methodological quality of each included study was independently assessed by 2 reviewers (H.A. and E.G.) with the Cochrane Collaboration risk of bias tool. Assessment included 7 specific domains (random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other biases). These domains were evaluated and characterized as high, low, or unclear risk of bias. Any disagreements were solved after discussion with the third reviewer (M.R.). The GRADE approach was utilized for quality rating of a body of evidence into high, moderate, low, and very low.
Data synthesis
The data analysis was performed using RevMan software 5.1 (2011; Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark) The results were combined using the fixed effects model. All specified outcomes were dichotomous and summarized by calculating the odds ratio (OR) with 95% confidence intervals (CIs). If any heterogeneity existed (by the χ 2 test, with P < .1), random effects model was employed. If I 2 was ≥50%, sensitivity analysis was performed by excluding the trials that potentially biased the results. Funnel plots were planned to test publication bias. Subgroup analysis was conducted by grouping the trials according to the type of the non-atypical EH: simple or complex.
The weighting coefficients of the studies were computed by Mantel-Haenszel method (default statistical method of metaanalysis programmed in RevMan) and based on the estimated effect measure. A pooled effect estimate was calculated as a weighted average of the intervention effects estimated in the individual studies according to the following formula:
weighted average = sum of ( estimate × weight ) sum of weights = ∑ Y i W i ∑ W i
Results
Study selection
The PRISMA flow diagram ( Figure 1 ) illustrates the search process. Of 229 articles screened, 19 studies were identified as potentially eligible for inclusion. Only 7 RCTs fulfilled the inclusion criteria. A total of 12 trials ( Table 1 ) were excluded for the following reasons: 5 studies were not RCTs; 3 RCTs compared oral progestins vs other treatment options rather than LNG-IUS; and 4 RCTs evaluated prophylactic use of LNG-IUS in tamoxifen-treated women.
| Study | Exclusion comments |
|---|---|
| Gallos ID, Krishan P, Shehmar M, Ganesan R, Gupta JK. LNG-IUS vs oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study. Hum Reprod 2013;28:2966-71. | Not RCT |
| Gallos ID, Ganesan R, Gupta JK. Prediction of regression and relapse of endometrial hyperplasia with conservative therapy. Obstet Gynecol 2013;121:1165-71. | Not RCT |
| Gallos ID, Krishan P, Shehmar M, Ganesan R, Gupta JK. Relapse of endometrial hyperplasia after conservative treatment: a cohort study with long-term follow-up. Hum Reprod 2013;28:1231-6. | Not RCT |
| Arnes M, Hvingel B, Orbo A. Levonorgestrel-impregnated intrauterine device reduces occurrence of hyperplastic polyps: a population-based follow-up cohort study. Anticancer Res 2014;34:2319-24. | Not RCT |
| Orbo A, Arnes M, Hancke C, Vereide AB, Pettersen I, Larsen K. Treatment results of endometrial hyperplasia after prospective D-score classification: a follow-up study comparing effect of LNG-IUD and oral progestins vs observation only. Gynecol Oncol 2008;111:68-73. | Not RCT |
| Ozdegirmenci O, Kayikcioglu F, Bozkurt U, Akgul MA, Haberal A. Comparison of the efficacy of three progestins in the treatment of simple endometrial hyperplasia without atypia. Gynecol Obstet Invest 2011;72:10-4. | RCT compared the efficacy of 3 oral progestins rather than LNG-IUS |
| Jarvela IY, Santala M. Treatment of nonatypic endometrial hyperplasia using thermal balloon endometrial ablation therapy. Gynecol Obstet Invest 2005;59:202-6. | RCT compared thermal balloon endometrial ablation to oral progestin rather than LNG-IUS |
| Yener C, Okan E, Mutluay S, Sengun Y. Comparison of 2 therapies in simple endometrial hyperplasia: oral medroxyprogesterone acetate vs depot GNRH agonist. Jinekoloji Obstet Dergisi 1997;11:143-6. | RCT compared oral progestin to depot GNRH agonist rather than LNG-IUS |
| Wong AW, Chan SS, Yeo W, Yu MY, Tam WH. Prophylactic use of levonorgestrel-releasing intrauterine system in women with breast cancer treated with tamoxifen: a randomized controlled trial. Obstet Gynecol 2013;121:943-50. | RCT addressing prophylactic use of LNG-IUS |
| Gardner FJ, Konje JC, Bell SC, et al. Prevention of tamoxifen induced endometrial polyps using a levonorgestrel releasing intrauterine system long-term follow-up of a randomized control trial. Gynecol Oncol 2009;114:452-6. | RCT addressing prophylactic use of LNG-IUS |
| Chan SSC, Tam WH, Yeo W, et al. A randomized controlled trial of prophylactic levonorgestrel intrauterine system in tamoxifen-treated women. BJOG 2007;114:1510-5. | RCT addressing prophylactic use of LNG-IUS |
| Gardner FJE, Konje JC, Abrams KR, et al. Endometrial protection from tamoxifen-stimulated changes by a levonorgestrel releasing intrauterine system: a randomized controlled trial. Lancet 2000;356:1711-17. | RCT addressing prophylactic use of LNG-IUS |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
